Uncovering a Predictive Biomarker for Alzheimer’s

Researchers publishing in Alzheimer’s and Dementia have published a correlation between the Alzheimer’s-linked protein tau and another protein, bisecting N-acetylglucosamine (GlcNAc), which suggests its usefulness as a biomarker.

The need for early prediction

This paper begins with a note that to be effective, Alzheimer’s treatment must begin before irrevocable neurodegeneration has already occurred [1]. Therefore, biomarkers for this destructive disease are necessary for its early diagnosis. Previous research has found that specific forms of tau can be found in blood, making them potentially useful for this purpose [2].

Changes in glycosylated proteins (such as GlcNAc) have been previously reported in Alzheimer’s disease, but this relationship has not been completely elucidated [3]. The researchers claim that they have previously shown that GlcNAc is higher in people with Alzheimer’s disease than people without it [4], which led them to do this research specifically on its potential value as a biomarker.

Interesting findings from a longitudinal cohort

Out of a total of 3363 participants in a wide-ranging Swedish study of people older than 60 years old, 233 people were randomly selected for inclusion. All of them were free from dementia at baseline. For a maximum of 17 years, participants under 78 years old were given follow-up assessments every 6 years and older participants were given these assessments every 3 years; all of these assessments contained medical examinations and neurological tests.

In people who did and did not develop Alzheimer’s disease, GlcNAc and tau were found to be significantly, although loosely correlated, with an r of 0.55 for the group that developed Alzheimer’s and an r of 0.27 for the group that did not. In people with full-blown Alzheimer’s, the correlation was even stronger, at 0.85. In people who were found to have developed Alzheimer’s at the first six-year followup, GlcNAc had remained relatively stable.

Interestingly, people with relatively high or low GlcNAc-to-tau ratios had significantly less chance of developing Alzheimer’s than people in the middle of the curve. At baseline, these groups did not have any other statistically significant differences, including age, sex, or mental state.

This study determined that having an intermediate GlcNAc-to-tau ratio is roughly as dangerous as having the Alzheimer’s-linked allele ApoE4. It also determined that people with both of these characteristics have five times the Alzheimer’s risk of people with neither of these characteristics.

Conclusion

When measured alongside tau, bisecting N-acetylglucosamine appears to be a strong biomarker. However, this study opens up several more questions, such as the physiological reasons behind the middle of a statistical group appearing to be more dangerous than the edges. The researchers note that Alzheimer’s was diagnosed clinically, rather than with biomarkers, which helps prevent circularity (using biomarkers to diagnose biomarkers) but does not define the specific characteristics of these Alzheimer’s patients particularly well. They suggest that more work should be done to determine the role of GlcNAc and its value as a biomarker of Alzheimer’s.

Literature

[1] Karran, E., Mercken, M., & Strooper, B. D. (2011). The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nature reviews Drug discovery, 10(9), 698-712.

[2] Karikari, T. K., Pascoal, T. A., Ashton, N. J., Janelidze, S., Benedet, A. L., Rodriguez, J. L., … & Blennow, K. (2020). Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. The Lancet Neurology, 19(5), 422-433.

[3] Gaunitz, S., Tjernberg, L. O., & Schedin-Weiss, S. (2021). What can N-glycomics and N-glycoproteomics of cerebrospinal fluid tell us about Alzheimer disease?. Biomolecules, 11(6), 858.

[4] Nagae, M., Kanagawa, M., Morita-Matsumoto, K., Hanashima, S., Kizuka, Y., Taniguchi, N., & Yamaguchi, Y. (2016). Atomic visualization of a flipped-back conformation of bisected glycans bound to specific lectins. Scientific Reports, 6(1), 22973.